A retrospective review of 48 individuals, including 12 families, molecularly diagnosed with hereditary leiomyomatosis and renal cell cancer (HLRCC).

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by autosomal dominant germline mutations in the fumarate hydratase (FH) gene and is characterized by cutaneous leiomyomas, uterine leiomyomas and aggressive renal malignancies. We conducted a retrospective chart review to characterize the patients referred to our Regional Genetics Program for assessment of HLRCC from 2004 to mid-2016. Forty-eight of 69 (69.5%) referred individuals were positive for a pathogenic or likely pathogenic variant in FH; they had an average age of 39.1 years. There were 11 different FH variants among them. As expected, the most sensitive indications for a positive genetic test were papillary renal cell carcinoma (RCC) at a young age (5/5; 100%) and multiple cutaneous leiomyomas (18/19; 95%). However, only twenty-two of 48 (46%) individuals with a positive molecular test had cutaneous leiomyomas, which is considerably lower than previously reported and supports the likelihood of ascertainment bias in previous reports. Notably, we have experience with 1 large family in which there were no cutaneous leiomyomas across a large age range. We confirm that multiple cutaneous leiomyomas and papillary RCCs at a young age have a high positive predictive value for a molecular diagnosis of HLRCC, but that cutaneous leiomyomas are less prevalent in HLRCC than previously understood, and therefore the condition is likely to be under-ascertained. Our understanding of the phenotypic spectrum of HLRCC is still evolving.

Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer.

CONTEXT: Hereditary diffuse gastric cancer is caused by germline mutations in the epithelial cadherin (CDH1) gene and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer. OBJECTIVE: To determine whether recurring germline CDH1 mutations occurred due to independent mutational events or common ancestry. DESIGN, SETTING, AND PATIENTS: Thirty-eight families diagnosed clinically with hereditary diffuse gastric cancer were accrued between November 2004 and January 2006 and were analyzed for CDH1 mutations as part of an ongoing study at the British Columbia Cancer Agency. Twenty-six families had at least 2 gastric cancer cases with 1 case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years. MAIN OUTCOME MEASURES: Classification of family members as carriers or noncarriers of CDH1 mutations. Haplotype analysis to assess recurring mutations for common ancestry was performed on 7 families from this study and 7 previously reported families with the same mutations. RESULTS: Thirteen mutations (6 novel) were identified in 15 of the 38 families (40% detection rate). The 1137G>A splicing mutation and the 1901C>T (A634V) missense/splicing mutation occurred on common haplotypes in 2 families but on different haplotypes in a third family. The 2195G>A (R732Q) missense/splicing mutation occurred in 2 families on different haplotypes. The 2064-2065delTG mutation occurred on a common haplotype in 2 families. Two families from this study plus 2 additional families carrying the novel 2398delC mutation shared a common haplotype, suggesting a founder effect. All 4 families originate from the southeast coast of Newfoundland. Due to concentrations of lobular breast cancer cases, 2 branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these 4 families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%). CONCLUSIONS: Recurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.